Inclusion Criteria:

• Patients will be initially assessed through a clinical interview by a specialized psychiatrist and subsequently by a second interviewer who will use the eligibility criteria and screening and diagnostic confirmation instruments below to delineate the sample universe, and must meet the following criteria before randomization:
• Diagnosis of MDD, in a single or recurrent, non-psychotic episode, as defined by the DSM-IV-TR through specialized clinical evaluation and confirmed by the Mini International Neuropsychiatric Interview (MINI - Amorim, 2000);
• The current depressive episode must have a duration of ≥ 8 weeks;
• Inadequate response to ≤ 2 attempts at pharmacological treatment for the current episode of MDD, including the treatment the patient is undergoing at the time of screening, with each attempt lasting a minimum of 4 to 6 weeks, with a first-line antidepressant (SSRI or SNRI) and with a minimum effective dose (defined by the package insert) or higher;
• Inadequate response is defined as: < 50% reduction in the severity of depressive symptoms, as measured by the subject's self-report score on the Visual Analogue Scale (VAS);
• Be between 18 and 60 years of age, inclusive;
• Have a score ≥ 24 on the Montgomery-Åsberg Depression Scale (MADRS);
• Have read and signed the informed consent form (Appendix 1) after the nature of the study has been fully explained and before any study-related procedures are performed;
• Female patients must be:
• Postmenopausal for at least one year, or;
• Surgically unable to conceive (having undergone hysterectomy or bilateral oophorectomy or tubal ligation or otherwise unable to conceive), or;
• Practicing an acceptable method of birth control (defined as: hormonal contraceptives, spermicide plus barrier, a single vasectomized partner and/or intrauterine device);
• If a potentially pregnant patient is practicing an acceptable method of birth control (as mentioned above), she must have a negative urine pregnancy test at enrollment, as well as at baseline, before receiving the study drug.

Exclusion Criteria:

• Potential patients who meet any of the following criteria will be prohibited from participating in the study:
• Known contraindication to brexpiprazole or known hypersensitivity;
• Individuals who report treatment with adjunctive antipsychotic medication to an antidepressant during the current major depressive episode;
• Individuals who have a history of ECT (electroconvulsive therapy) treatment at any time in the past or present, or who have received vagus nerve stimulation or an implanted deep brain stimulation device for the treatment of treatment-resistant depression;
• Individuals currently requiring hospitalization or who have been hospitalized in the four weeks prior to screening for the current major depressive episode;
• Exposure to any other experimental drug or device in the 30 days prior to inclusion, except for previously described antidepressant use;
• Use of benzodiazepines and/or hypnotics (including non-benzodiazepine inducers) within 1 week prior to the start of the study, but excluding short-acting non-benzodiazepine sleep inducers (i.e., zolpidem, zaleplon, zopiclone, and eszopiclone only);
• Pregnancy, breastfeeding, or patients intending to become pregnant during the study;
• Evidence of renal impairment, defined as serum creatinine levels > 133 mmol/L in men, > 124 mmol/L in women, which correspond to > 1.51 mg/dL and > 1.41 mg/dL, respectively, at Week 1 of inclusion;
• Evidence of clinically significant hepatic impairment (defined as AST or ALT > 2 times the upper limit of normal) at Week 1 of inclusion;
• Significant cardiovascular disease, including a history of myocardial infarction in the last 5 years, stroke, clinically significant valvular heart disease, unstable angina, clinically abnormal ECG, arrhythmia, or congestive heart failure, resulting in cardiovascular disability functional class III or IV (NYHA, 1964);
• Uncontrolled hypertension (defined as a diastolic blood pressure ≥ 100 mmHg and/or a systolic blood pressure ≥ 180 mmHg with or without medication).

Hypertensive patients receiving medication must have been receiving the same dose of the same antihypertensive medication for at least two months;

-Evidence of uncontrolled thyroid disorders, including hyper- or hypothyroidism or abnormal TSH levels. Patients known to be on thyroid hormone replacement therapy must have been on a stable dose for at least three months prior to inclusion and have a normal TSH level at inclusion;